rs387906493

chrX-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-GchrX-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-GCGGCCGCGGCTGCCGCGGCGGCCCCGGCCGCGGCTGCCGCGGCGGCCC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BP6_Very_Strong

The NM_139058.3(ARX):c.428_451del(p.Gly143_Ala150del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 794,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000019 (0 hom. 4 hem.)
• Consequence: ARX NM_139058.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09

Genes affected

ARX (HGNC:18060): (aristaless related homeobox) This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_139058.3.
• BP6: Variant X-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-G is Benign according to our data. Variant chrX-25013543-GCGGCCGCGGCTGCCGCGGCGGCCC-G is described in ClinVar as [Likely_benign]. Clinvar id is 1235070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARX	NM_139058.3	c.428_451del	p.Gly143_Ala150del	inframe_deletion	2/5	ENST00000379044.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARX	ENST00000379044.5	c.428_451del	p.Gly143_Ala150del	inframe_deletion	2/5	1	NM_139058.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000959 AC: 1 AN: 104289 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 29767

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000200

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000188 AC: 13 AN: 690639 Hom.: 0 AF XY: 0.0000191 AC XY: 4 AN XY: 209747

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000210

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000959 AC: 1 AN: 104289 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 29767

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000200

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2020

- -

Intellectual disability, X-linked, with or without seizures, arx-related;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906493; hg19: chrX-25031660;